In modern society stress and its consequences are prevalent and result in considerable distress and alterations in physical health and social and occupational functioning. At its extreme, stress can lead to disabling neuropsychiatric problems which include depression, anxiety disorders, post-traumatic stress disorder and other illnesses (Mitchell, 1998; Arborelius et al., 1999). Recent studies demonstrate the potent effects of stress on the body and brain. For example, chronic and intense stress can result in alterations in the region of the brain that plays an important role in memory (McGaugh and Roozendaal, 2002). In addition, stress can negatively impact cardiovascular function, immune function and gastrointestinal physiology (Tache et al., 2001; Beglinger and Degen, 2002; Coste et al., 2002; Gasparotto et al., 2002; Vanitallie, 2002).
It is estimated that 10% of the population suffers from depression and another 15% from clinically significant anxiety. This high incidence of stress-related problems is reflected by the fact that approximately 50% of visits to primary care doctors are stress and/or psychologically related.
Current treatments for stress and its disorders are highly sought after and include the traditional anti-anxiety drugs like Valium and Xanax. More recently newer antidepressants like Prozac have been used to treat depression, anxiety and other stress related problems. It is estimated that $13 billion was spent last year in the U.S. on drugs like Prozac and Paxil. However, these treatments still suffer from lack of efficacy in approximately 30% of the individuals treated. Among those who do respond, only about 50% of them will return to normal function. In addition, these treatments have bothersome side-effects (50% have marked sexual dysfunction) which make treatment with these drugs unacceptable for many individuals. Since depression and anxiety are recurrent and chronic disorders it is important that patients are comfortable taking their medication over a long period of time. Overactivity of the corticotropin-releasing factor (CRF) system is implicated in depression and anxiety and treatments aimed at this system may be very effective (Reul and Holsboer, 2002).
Studies in animals demonstrate that antagonism of the CRF system blocks the distress and physical effects related to stress (Takahashi et al., 2001; Bakshi et al., 2002). Studies in humans show that the CRF system in the brain is overactive in patients with depression, anxiety disorders and other neuropsychiatric problems (Nemeroff, 1989; Chappell et al., 1996; Fossey et al., 1996; Bremner et al., 1997; Mitchell, 1998; Baker et al., 1999). In addition, human and animal studies demonstrate that many effective antidepressant treatments decrease brain CRF activity (Veith et al., 1993). Based on these findings the pharmaceutical industry is currently intensively searching for orally administered compounds that will block or reduce the effects of CRF in the brain. Already some compounds have been identified and are in the early stages of human studies (Zobel et al., 2000).
The CRF system is now known to consist of at least seven components. CRF is a neurotransmitter that is released from neurons and has its effects by interacting with CRF receptors located on adjacent brain cells. Urocortin (UCN), urocortin II (UCN II) and urocortin III (UCN III) are other neurotransmitters similar to CRF that also interact with the system (Vaughan et al., 1995; Lewis et al., 2001; Reyes et al., 2001). Once stimulated the receptors activate intracellular processes which mediate the stress effects.
CRF produces its effects by interacting with two different receptors termed CRF1 and CRF2 (Chen et al., 1993; Penin et al., 1995). Multiple isoforms of the two receptors exist. For example, there are three different isoforms of the CRF2 receptor, termed “CRF2α,” “CRF2β” and “CRF2γ” (Lovenberg et al., 1995; Kostich et al., 1998). In addition to CRF1 and CRF2 receptors, there also exists a protein that is found in brain cells that functions to inactivate CRF after it is released termed “CRF binding protein” (Potter et al., 1991).
While much is known about the biology of CRF, considerably less is understood about the urocortin family of peptides. To date three different urocortin peptides have been identified: UCN, UCN II and UCN III. These peptides are likely to be important in mediating stress-induced behavior because it has been found that CRF knockout mice exhibit normal stress-induced behavioral responses that are blocked by CRF receptor antagonism (Weninger et al., 1999). UCN is found in several brain regions that contain R2α (Kozicz et al., 1998; Bittencourt et al., 1999). UCN II and UCN III are highly selective for R2α (Lewis et al., 2001; Reyes et al., 2001). UCN II mRNA is found in the supraoptic and arcuate hypothalamic nuclei and in the locus coeruleus, rostral pons, and motor nuclei. UCN III is found in the hypothalamus, amygdala, and brainstem of rats, and is the rodent analog of the newly discovered human peptide, stresscopin (Hsu and Hsueh, 2001).